Staphylococcus aureus is a common cause of healthcare-associated bloodstream infections and community acquired skin infections. The morbidity and mortality caused by this pathogen is further compounded by the increasing rates of drug-resistance, which make S. aureus infections difficult to treat. Nasal carriage of this pathogen, which occurs asymptomatically in around 30% of individuals in the United States at any one time, is a major risk factor for healthcare-associated bloodstream infections. The nasal reservoir is therefore an important target for medical interventions aimed at preventing these deadly infections. As the use of antibiotics can further drive pressure for resistance, there is a lack of safe and effective measures for decolonization of S. aureus in the anterior nares. Interestingly, the presence of certain other microbes in the nares (e.g. Streptococcus pneumoniae and Staphylococcus epidermidis) has been shown to be associated with a reduction in colonization by S. aureus, and yet a full characterization of how nasal microbial ecology affects S. aureus has yet to be done. There is particularly a lack of knowledge of how the predominant members of the nasal microbiome (Firmicutes, Actinobacteria and Proteobacteria) interact with S. aureus to prevent or facilitate colonization. The study proposed here therefore aims to globally characterize associations between S. aureus and the residents of the nasal microbiome. By taking advantage of recent advances in sequencing technology and analysis methods for human microbial communities, this study will identify microbial taxa in addition to functions encoded by the nasal microbial metagenome. By applying both cross-sectional and longitudinal methods to a large cohort of adults, Aim 1 will identify nasal microbiome characteristics that are associated with individuals' S. aureus nasal carriage patterns (persistent, transient or non-carrier) and with the acquisition, carriage and loss of S. aureus. Aim 2 will apply similar methods to a large cohort of infants followed monthly during the first year of life, and will identify nasal microbiome characteristics associated with acquisition, carriage and loss of S. aureus in the highly dynamic infant microbiome. We anticipate that the proposed study will identify novel species, genes and functional pathways that are associated with nasal carriage of S. aureus and that these leads could be followed up in controlled laboratory investigations in pursuit of innovative antibiotic-independent decolonization approaches.